Process for preparation of 5H-dibenzo[a,d] cycloheptene derivatives

Abstract

A process for preparation of protriptyline hydrochloride from 5-dihydrobenzocycloheptatriene of formula (1) by coupling with chloropropyl alcohol in the presence of excess n-butyl Lithium in tetrahydrofuran under inert atmosphere, followed by preparation of mesylate derivative of formula (3) and finally the nucleophilic displacement of the mesylate group by reacting methylamine solution in methanol to give protriptyline free base of the formula (4). Also the present process reveals the hydrochloride salt formation and purification of the same to give pure pharmaceutical grade protriptyline hydrochloride with impurities less than 0.1% w/w.

1. A process of preparing N-methyl-5H-dibenzo (a,d)-cycloheptene-5-propanamine hydrochloride comprising reacting 5-dihydro dibenzocycloheptatriene with chloro propyl alcohol in the presence of an excess of n-butyl lithium to obtain 3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol, converting the resulting product to a compound having the formula 
       
         
           
           
               
               
           
         
       
       wherein R is a leaving group, reacting the compound of formula (3) with methylamine solution in methanol to produce 5-(N-methyl-aminopropyl) dibenzocycloheptatriene and converting 5-(N-methyl-aminopropyl) dibenzocycloheptatriene to N-methyl-5H-dibenzo (a,d)-cycloheptene-5-propanamine hydrochloride. 
     
     
       2. The process according to  claim 1  wherein R denotes a mesylate, a tosylate, a besylate or an acetyl group. 
     
     
       3. The process according to  claim 1 , the conversion of 5-(N-methyl-aminopropyl) dibenzocycloheptatriene to N-methyl-5H-dibenzo (a,d)-cycloheptene-5-propanamine hydrochloride comprising dissolving 5-(N-methyl-aminopropyl) dibenzocycloheptatriene in isopropyl ether, and adding to the solution HCl solution in ether. 
     
     
       4. A process of purifying N-methyl-5H-dibenzo (a,d)-cycloheptene-5-propanamine hydrochloride prepared according to  claim 1  comprising leaching the compound with toluene and a compound selected from the group consisting of hot acetone, acetonitrile and ethyl acetate. 
     
     
       5. The process of  claim 1  wherein the step of preparing 3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-propan-1-ol comprises using 4 eq. of n-butyllithium and 1.05 eq. of 3-chloropropyl alcohol. 
     
     
       6. The process according to  claim 1  wherein the step of preparing the compound of formula (3) comprises using 1.5 eq. of an organic base and 1.2 eq. of a compound selected from the group consisting of methane sulfonyl chloride, toluene sulfonyl chloride and benzene sulfonyl chloride in tetrahydrofuran. 
     
     
       7. The process according to  claim 6  wherein said organic base is triethyl amine.